21-hydroxylase deficiency is a genetic disorder of adrenal steroid biosynthesis caused by mutations in the human 21-hydroxylase gene (CYP21A2), leading to decreased cortisol production and excess production of androgens, as well as "salt wasting" in some affected individuals. There are 3 forms: 2 classic types, salt-wasting (SW) and simple virilizing (SV), and a nonclassic (NC) late-onset type. The classic types are manifest at birth and are characterized by severe enzyme deficiency and prenatal onset of virilization, resulting in ambiguous genitalia in females; the SW form, which is due to inadequate aldosterone production and affects 75% of patients with classic type, can be life-threatening. The NC type can present any time postnatally and is milder; females are not virilized at birth.

SW – Characterized in neonates by failure to thrive, hyperkalemia, and hyponatremia. Females present with varying levels of ambiguous genitalia. Other signs and symptoms include poor feeding, vomiting, dehydration, and weight loss. Neonates are at risk for adrenal crisis, particularly males who are at risk for missed diagnosis due to normal genitalia, absent newborn screening.

SV – Female neonates present with ambiguous genitalia. Without therapy, both males and females will begin to show effects of androgen excess (eg, acne, rapid growth, advanced bone age, premature pubic and axillary hair).

NC – Milder, and may present any time postnatally with signs of androgen excess. In females, this may manifest with hirsutism, menstrual irregularities, and infertility. Males are less affected. May be asymptomatic.

Management is multidisciplinary and may include glucocorticoid or mineralocorticoid therapy, replacement salt (sodium chloride), patient and family education and counseling, hormone replacement, reconstructive surgery (genitoplasty, vaginal dilation), and monitoring for complications.

See also congenital adrenal hyperplasia.